Asthma remains a substantial public health in the United States and worldwide, with approximately 6.7% of adults and 8.5% of children under 18 years of age affected with asthma. The morbidity associated with asthma continues despite significant advances in the understanding of asthma pathogenesis and treatment strategies. Over the past 15 years, the NIH-supported asthma networks, ACRN and CARE, have added to the evidence base for asthma diagnosis and therapeutics, and this evidence has been prominently incorporated into national and international guidelines for asthma management. Despite this growing knowledge base, there remain numerous unanswered questions in asthma care ranging from strategies to optimize care based upon individual patient characteristics (personalized medicine) to examination of novel therapeutic approaches to improve asthma control. This proposal contains clinical trials directed at three diverse, and understudied asthma populations: preschool children with mild-moderate persistent symptomatic asthma, adolescents and adults with asthma inadequately controlled with low dose inhaled corticosteroids (ICS), and adults with severe persistent asthma which remains uncontrolled despite maximum standard therapy. We will examine two therapeutic strategies for preschool children with mild-moderate asthma and whether the incorporation of a biomarker (fractional concentration of exhaled nitric oxide) allows for prediction of the more effective treatment strategy. We also propose to examine the addition of high dose Vitamin D to ICS in adult subjects with not well-controlled asthma and vitamin D insufficiency to evaluate if the Vitamin D improves corticosteroid responsiveness and provides superior asthma control to doubling the dose of ICS or similar control to the addition of a long-acting p-agonist. In concert with this study, we propose to evaluate the potential mechanisms by which Vitamin D enhances corticosteroid effectiveness. Lastly, given the morbidity associated with severe asthma and failure to respond to current therapy, we propose a trial examining the safety and efficacy of a novel immunomodulatory agent, abatacept, which inhibits the delivery of a co-stimulatory signal (through CD28) required for T-cell activation, in subjects with severe persistent uncontrolled asthma. In summary, these studies address current gaps in the evidence base for asthma treatment decision making as well as explore novel therapeutic strategies in patients in whom inadequate asthma control remains commonplace.